8.A.127.  The Receptor Activity-Modifying Protein (RAMP) Family 

RAMPs (1-3) in humans are proteolytically processed, single transmembrane, accessory proteins, crucial for plasma membrane expression, but they also determine receptor phenotype of various G-protein-coupled receptors (Bomberger et al. 2005). For example, adrenomedullin receptors are comprised of RAMP2 or RAMP3 (AM1R and AM2R, respectively) and the calcitonin receptor-like receptor (CRLR; Q16602; TC# 9.A.14.4.12), while a CRLR heterodimer with RAMP1 yields a calcitonin gene-related peptide receptor. The PDZ type I domain, present in the C terminus of RAMP3, but not in RAMP1 or RAMP2, leads to protein-protein interactions that determine receptor trafficking. The CRLR-RAMP complex undergoes agonist-stimulated desensitization and internalization and fails to resensitize (i.e. degradation of the receptor complex). Co-expression of N-ethylmaleimide-sensitive factor (NSF) with the CRLR-RAMP3 complex, but not CRLR-RAMP1 or CRLR-RAMP2 complex, altered receptor trafficking to a recycling pathway. Mutational analysis of RAMP3, by deletion and point mutations, indicated that the PDZ motif of RAMP3 interacts with NSF to cause the change in trafficking. The role of RAMP3 and NSF in AM2R recycling was confirmed in rat mesangial cells, where RNA interference with RAMP3 and pharmacological inhibition of NSF both resulted in a lack of receptor resensitization/recycling after agonist-stimulated desensitization. Thus, functional differences between the AM1R and AM2R occur at the level of post-endocytic receptor trafficking (Bomberger et al. 2005).



Bomberger, J.M., N. Parameswaran, C.S. Hall, N. Aiyar, and W.S. Spielman. (2005). Novel function for receptor activity-modifying proteins (RAMPs) in post-endocytic receptor trafficking. J. Biol. Chem. 280: 9297-9307.

Steiner, S., W. Born, J.A. Fischer, and R. Muff. (2003). The function of conserved cysteine residues in the extracellular domain of human receptor-activity-modifying protein. FEBS Lett. 555: 285-290.


TC#NameOrganismal TypeExample

Receptor activity-modifying protein 1, RAMP1, of 148 aas and 1 C-terminal TMS.  It is probably truncated by a protease that cleaves off the N-terminal leader sequence (Bomberger et al. 2005). RAMP1 is associated with the calcitonin-like receptor (CLR) and reveals a calcitonin gene-related peptide (CGRP) receptor. The extracellular region of RAMP1 contains six conserved cysteines. Cys-40, 57, 72 and 104 are required the transport of hRAMP1 together with the CLR to the cell surface (Steiner et al. 2003). 

RAMP1 of Homo sapiens


RAMP2 of 175 aas and 2 TMSs, N- and C-terminal. For description, see the family description.

RAMP2 of Homo sapiens


RAMP3 of 148 aas and 1 C-terminal TMS.


RAMP of 139 aas and 1 C-terminal TMS

RAMP of Monopterus albus (swamp eel)


TC#NameOrganismal TypeExample

Receptor activity-modifying protein 1-like of 172 aas and 2 TMSs, N- and C-terminal.

RAMP1 of Cuculus canorus


Receptor activity-modifying protein 1 isoform XI of 180 aas and 1 (C-terminal) or 2 (both N- and C-terminal).

RAMP of Anolis carolinensis


Uncharacterized protein of 140 aas and 2 TMSs, N- and C-terminal.

UP of Branchiostoma floridae


Uncharacterized protein of 226 aas and 2 TMSs, N- and C-terminal.

UP of Melopsittacus undulatus (budgerigar)


TC#NameOrganismal TypeExample

Uncharacterized protein of 206 aas and 0 TMSs/

UP of Microvirga massiliensis